title: A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy.
abstract: The in vivo therapeutic efficacy of DC-based cancer vaccines is limited by suboptimal DC maturation protocols. Although delivery of TLR adjuvants systemically boosts DC-based cancer vaccine efficacy, it could also increase toxicity. Here, we have engineered a drug-inducible, composite activation receptor for DCs (referred to herein as DC-CAR) comprising the TLR adaptor MyD88, the CD40 cytoplasmic region, and 2 ligand-binding FKBP12 domains. Administration of a lipid-permeant dimerizing ligand (AP1903) induced oligomerization and activation of this fusion protein, which we termed iMyD88/CD40. AP1903 administration to vaccinated mice enabled prolonged and targeted activation of iMyD88/CD40-modified DCs. Compared with conventionally matured DCs, AP1903-activated iMyD88/CD40-DCs had increased activation of proinflammatory MAPKs. AP1903-activated iMyD88/CD40-transduced human or mouse DCs also produced higher levels of Th1 cytokines, showed improved migration in vivo, and enhanced both antigen-specific CD8+ T cell responses and innate NK cell responses. Furthermore, treatment with AP1903 in vaccinated mice led to robust antitumor immunity against preestablished E.G7-OVA lymphomas and aggressive B16.F10 tumors. Thus, the iMyD88/CD40 unified "switch" effectively and safely replaced exogenous adjuvant cocktails, allowing remote and sustained DC activation in vivo. DC "licensing" through iMyD88/CD40 may represent a mechanism by which to exploit the natural synergy between the TLR and CD40 signaling pathways in DCs using a single small molecule drug and could augment the efficacy of antitumor DC-based vaccines.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Priyadharshini
authors.initials: P
authors.lastname: Narayanan
authors.forename: Natalia
authors.initials: N
authors.lastname: Lapteva
authors.forename: Mamatha
authors.initials: M
authors.lastname: Seethammagari
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Levitt
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Slawin
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019013:CD40 Antigens / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D009930:Organic Chemicals / Q000008:administration & dosage; D015202:Protein Engineering; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D019496:Cancer Vaccines; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009930:Organic Chemicals; D051193:Toll-Like Receptors; D022061:Tacrolimus Binding Protein 1A; C423866:AP 1903 reagent